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Discovery of New Anti-MRSA Agents Based on Phenoxyethanol and Its Mechanism
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2022-10-18 , DOI: 10.1021/acsinfecdis.2c00365 Jinxin Xie 1 , Lijuan Wang 1 , Xiaoyong Zhang 2 , Yiyang Li 2 , Xin Liao 1 , Caixin Yang 1 , Ri-Yuan Tang 1, 3
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2022-10-18 , DOI: 10.1021/acsinfecdis.2c00365 Jinxin Xie 1 , Lijuan Wang 1 , Xiaoyong Zhang 2 , Yiyang Li 2 , Xin Liao 1 , Caixin Yang 1 , Ri-Yuan Tang 1, 3
Affiliation
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Methicillin-resistant Staphylococcus aureus (MRSA) poses a severe threat to public health and safety. The discovery and development of novel anti-MRSA drugs with a new mode of action are a challenge. In this study, a class of novel aryloxyethyl propiolates and their homologues as anti-MRSA agents have been designed and synthesized based on phenoxyethanol, of which compound II-39 showed high inhibitory activity against MRSA with an MIC of 0.78 μg/mL and an MBC of 3.13 μg/mL, which was better than that of vancomycin. Compound II-39 could destroy the cell wall and cell membrane, inhibited the formation of a biofilm, and bound to the DNA of MRSA through the electrostatic and groove interaction. Proteomic and metabolomic studies revealed that compound II-39 affected multiple intracellular metabolic pathways of MRSA. Notably, compound II-39 could effectively inhibit the expression of CrtPQMN proteins and block the biosynthesis of virulence factor (staphyloxanthin). Thus, aryloxyethyl propiolates and their homologues are promising anti-MRSA agents with multiple targets.
中文翻译：
基于苯氧乙醇的新型抗MRSA药物的发现及其作用机制
耐甲氧西林金黄色葡萄球菌(MRSA) 对公众健康和安全构成严重威胁。发现和开发具有新作用模式的新型抗 MRSA 药物是一项挑战。本研究基于苯氧乙醇设计合成了一类新型芳氧乙基丙炔酸酯及其同系物作为抗 MRSA 药物，其中化合物II-39对 MRSA 具有较高的抑制活性，MIC 为 0.78 μg/mL，MBC 3.13 μg/mL，优于万古霉素。化合物II-39可以破坏细胞壁和细胞膜，抑制生物膜的形成，通过静电和沟槽相互作用与MRSA的DNA结合。蛋白质组学和代谢组学研究表明，化合物II-39影响 MRSA 的多种细胞内代谢途径。值得注意的是，化合物II-39可有效抑制 CrtPQMN 蛋白的表达并阻断毒力因子（葡萄黄素）的生物合成。因此，芳氧乙基丙炔酸酯及其同系物是有前途的多靶点抗 MRSA 药物。
更新日期：2022-10-18
中文翻译：
基于苯氧乙醇的新型抗MRSA药物的发现及其作用机制
耐甲氧西林金黄色葡萄球菌(MRSA) 对公众健康和安全构成严重威胁。发现和开发具有新作用模式的新型抗 MRSA 药物是一项挑战。本研究基于苯氧乙醇设计合成了一类新型芳氧乙基丙炔酸酯及其同系物作为抗 MRSA 药物，其中化合物II-39对 MRSA 具有较高的抑制活性，MIC 为 0.78 μg/mL，MBC 3.13 μg/mL，优于万古霉素。化合物II-39可以破坏细胞壁和细胞膜，抑制生物膜的形成，通过静电和沟槽相互作用与MRSA的DNA结合。蛋白质组学和代谢组学研究表明，化合物II-39影响 MRSA 的多种细胞内代谢途径。值得注意的是，化合物II-39可有效抑制 CrtPQMN 蛋白的表达并阻断毒力因子（葡萄黄素）的生物合成。因此，芳氧乙基丙炔酸酯及其同系物是有前途的多靶点抗 MRSA 药物。
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